Tyrosyl phosphorylation is a mechanism involving in regulation of human cellular processes from cell differentiation and growth to apoptosis. The process of tyrosyl phosphorylation is regulated by protein-tyrosine phosphatases (PTP) and protein-tyrosine kinases (PTK). When this regulation is disrupted, diseases such as cancer can arise (Mohi and Neel, 2007). Although there is more research on PTKs since the first PTK was discovered about 10 years earlier than the first PTP, recent studies have found that PTPs have a prominent role in regulation of tyrosyl phosphorylation in the cells (Alonso et al., 2004).
Shp2, encoded by the PTPN11 gene, is found to be mutated in several types of leukemias (Mohi and Neel, 2007). Furthermore, the wildtype Shp2 mediates cell signaling of many protein tyrosine kinase oncogenes such as ErbB and Met. Shp2 is necessary for embryonic development and for growth factor, cytokine, and extra-cellular matrix signaling (Salmond and Alexander, 2006) and is involved in regulation of cell proliferation, differentiation, and migration. Shp2 mutations are linked to Noonan syndrome, juvenile myelomonocytic leukemia, acute myelogenous leukemia, and LEOPARD (lentigines, electrocardiogram abnormalities, ocular hypertelorism, pulmonic valvular stenosis, abnormalities of genitalia, retardation of growth, and deafness) syndrome.
Within these diseases, Shp2 is activated and interacts with the Gab family of docking proteins. This interaction activates a pathway leading to cell proliferation and tumorigenesis. The identification of Shp2's role in these diseases is very important for developing cancer therapy. Targeting and inhibiting Shp2 with small molecule inhibitors has become a major goal in developing a new cancer therapy.
Currently, there are a few known inhibitors of Shp2. Two of these compounds are CDL 4340-0580 (Hellmuth et al., 2008) and NAT6-297775, seen in FIGS. 1A and 1B (Noren-Muller et al., 2006). Although these compounds have the ability to inhibit Shp2, they also inhibit tumor suppressor Shp1, which is not the cause of these malignancies. Ultimately, a Shp2 inhibitor should only affect Shp2 and not other important cellular processes.